Research over the past 2 decades has suggested that significant differences exist
in the action potentials of endocardial, epicardial, and mid‐myocardial (M) cells
that comprise the ventricular myocardium. Relative differences in the time course
of repolarization of these 3 cell types, referred to as transmural dispersion of repolarization
(TDR), is largely responsible for the inscription of the T wave on the electrocardiogram
(ECG). Both the morphology and duration of the T wave appear to represent underlying
heterogeneity in repolarization, a process initially linked to increased risk of arrhythmia
and sudden death in patients with congenital long QT‐syndrome (LQTS). It is increasingly
apparent that repolarization heterogeneity is present in a variety of cardiovascular
diseases and syndromes and is even predictive of sudden death in the general population.
Furthermore, repolarization heterogeneity has also been associated with abnormalities
in myocardial mechanics, a finding that may have direct implications for understanding
the pathophysiology and treatment of heart failure. This review will focus on summarizing
current understanding of repolarization heterogeneity, with particular focus on clinical
implications.
Physiology of Myocardial Repolarization Heterogeneity
It has been nearly 3 decades since the description of the M cell reframed understanding
that regional differences exist in the electrical properties of the ventricular myocardium.
Canine models developed in the early 1990s for studying ventricular action potentials
first identified electrophysiologically distinct mid‐myocardial cells, termed M cells,
which were found to exhibit unique repolarization properties compared to the cells
contained in the endocardium and epicardium.1, 2 M cells are similar to epicardial
and endocardial cells histologically, but electrophysiologically and pharmacologically
appear to be a hybrid between Purkinje and ventricular cells. The hallmark of the
M cell is the characteristic of its action potential (AP) to prolong disproportionately
relative to the action potential of other ventricular myocardial cells in response
to heart rate slowing and action potential duration (APD)‐prolonging agents.1
The ionic basis for these M‐cell features include the presence of a smaller slowly
activating delayed rectifier potassium (K+) current (IKs), a larger late sodium (Na+)
current, and a larger Na+‐calcium (Ca2+) exchange current.3, 4 Accordingly, there
are prominent differences between M cells and the surrounding myocardial cells in
the response to various drugs. Alpha‐adrenergic agonists, such as phenylephrine, produce
a prolongation of Purkinje APD, whereas they abbreviate the M‐cell APD.5 Rapidly activating
delayed rectifier K+ current (IKr) blockers, including d‐sotalol and erythromycin,
produce a much greater prolongation of APD in M cells than cells in the epicardium
or endocardium. Other differences include the mechanisms of development of early afterdepolarizations
(EADs). EADs induced in the M cell are more sensitive to changes in intracellular
Ca2+ levels, whereas EADs elicited in Purkinje cells are not.6 These differences at
the cellular level allow for development of larger regional repolarization variations
that were finally demonstrated in vitro through development of an arterially perfused
myocardial wedge preparation.
In vivo models in dogs and rabbits have the disadvantage of requiring anesthesia,
which can directly affect myocardial conduction and repolarization.7, 8 Anesthetics,
including sodium pentobarbital, were found to be protective of torsades de pointes
(TdP) in dogs, whereas halothane offered no protection.7, 8 Development of an arterially
perfused left ventricular (LV) myocardial wedge preparation allowed for examination
of the interaction between these cell types under physiological conditions, without
the confounding effects of anesthesia (Figure 1).9 The qualitative differences between
the 3 ventricular cell types previously described in isolated tissues and cells are
present in the intact canine LV wall preparations.9 TDR is the result of intrinsic
differences in APD of cells spanning the ventricular wall. In the absence of electrolyte
or pharmacological provocation, myocytes isolated from the M region display APDs as
much as several 100 ms longer than those recorded from the endocardium or epicardium.
As a result, transmural dispersion represents the net differences in repolarization
times between these distinct action potentials. Accordingly, drugs such as sotalol
and erythromycin, which preferentially prolong M‐cell APD, will increase dispersion
of repolarization dramatically.10
Figure 1
Arterially perfused left ventricular wedge model of canine myocardium. Schematic diagram
of the arterially perfused canine LV wedge preparation. The wedge is perfused by a
small native branch of the left descending coronary artery and stimulated from the
endocardial surface. Transmembrane action potentials are recorded simultaneously from
epicardial (Epi), M region (M), and endocardial (Endo) sites using three floating
microelectrodes. A transmural ECG is recorded along the same transmural axis across
the bath, registering the entire field of the wedge. Reproduced with permission from
Yan et al.9 Promotional and commercial use of the material in print, digital, or mobile
device format is prohibited without the permission from the publisher Wolters Kluwer
Health. ECG indicates electrocardiogram; LV, left ventricular.
Subsequent studies found that the currents flowing adjacent to M cells are, in large
part, responsible for the morphology of the ECG T wave (Figure 2).10 The interplay
between these opposing currents determines the height of the T wave as well as the
degree to which either the ascending or descending limb of the T wave is interrupted,
causing a bifurcated or notched appearance (Figure 3).10 Under basal conditions, the
epicardial cells are always the earliest to repolarize and the M cells are the last.
Full repolarization of the M‐cell region marks the end of the T wave.10 The time interval
between the peak and end of the T wave, referred to as Tpeak−Tend (TpTe), therefore
represents the surface ECG manifestation of dispersion of repolarization across the
ventricular wall, hereafter referred to as repolarization heterogeneity.
Figure 2
Cellular basis for normal T‐wave inscription. Shown here is the temporal relationship
between transmembrane action potentials recorded from epicardial, M region, and endocardial
(A) or subendocardial Purkinje fiber regions (B). Note that M cell repolarization
is aligned with end of the T wave, whereas repolarization of the epicardial cells
is coincident with the peak of the T wave. ECG indicates electrocardiogram; Endo,
endocardial; Epi, epicardial; M Cell, Masonic myocardial Moe cell. Reproduced with
permission from Yan et al.10 Promotional and commercial use of the material in print,
digital, or mobile device format is prohibited without the permission from the publisher
Wolters Kluwer Health.
Figure 3
Transmural dispersion of repolarization. Shown here are the baseline (A) and sotalol‐induced
changes (B) in APD of each layer of the canine left ventricular arterially perfused
wedge. Note the disproportionately prolonged M‐cell action potential and its corresponding
contribution to the prolongation of the time from the peak to the end of the T wave
(Tpeak−end). Note as well the bifurcated or notched T‐wave morphology. The bottom
of the figure shows the calculated voltage differences between epicardial and M‐cell
APs (M‐Epi) and between the M‐cell and endocardial responses (Endo‐M) (bottom). AP
indicates action potential; APD, action potential duration; ECG, electrocardiogram;
Endo, endocardial; Epi, epicardial; M Cell, Masonic myocardial Moe cell. Reproduced
with permission from Yan et al.10 Promotional and commercial use of the material in
print, digital, or mobile device format is prohibited without the permission from
the publisher Wolters Kluwer Health.
Electrocardiographic Assessment of Repolarization Heterogeneity
The most often used ECG markers for measuring repolarization heterogeneity include
TpTe and QT dispersion (QTD). TpTe is calculated by measuring the interval from the
peak of the T wave to its offset. The offset of the T wave is frequently defined as
the intersection of the tangent to the steepest portion of the terminal portion of
the T wave and the isoelectric line.11 Most typically, lead V5 is used because previous
studies have suggested that precordial leads best reflect repolarization heterogeneity
across the ventricular wall, in contrast to limb leads, which reflect apical‐basal
or interventricular spatial heterogeneity.12 A large increase in TDR is likely to
be arrhythmogenic because the dispersion of repolarization and refractoriness occurs
over a very short distance (the width of the ventricular wall), creating a steep repolarization
gradient. Difficulties can arise in measuring the exact duration of TpTe, particularly
with low T‐wave amplitude, or when T waves are notched or biphasic.9, 13
Whereas the canine wedge model suggested that TpTe was an accurate measure of “transmural”
dispersion, studies of in vivo animal models have suggested that the generation of
the T wave may be more complex. Work done by Xia et al. revealed that in open‐chest
pig models, the peak of the T wave often occurred 30 to 40 ms before the full repolarization
of the epicardium. They concluded that the peak of the T wave likely represented a
summation of repolarization gradients both transmurally and apicobasally.14 Opthof
et al. also showed that TpTe intervals did not correlate with TDR, but did correlate
with global dispersion of repolarization in the whole heart.15 Validation of TpTe
as a direct measure of TDR is still debated, but most studies agree that TpTe provides
at least some measure of spatial dispersion or repolarization heterogeneity.
Another potential measure of TDR is QTD. QTD is calculated as the difference between
the maximum and minimum QT intervals measured on all 12 leads of the ECG. Reported
values of QTD vary widely, with studies showing normal values between 10 and 71 ms.16
Work in rabbits revealed that QTD showed significant correlation with dispersion of
monophasic AP.17 Higham et al. found a high positive correlation between the monophasic
action potentials and ECG dispersion indices.18 There has been argument, however,
that the main cause of QTD may, in fact, be the unreliable localization of the T‐wave
offset in patients with abnormal T waves.19 This was underscored in a study by Malik
et al., which revealed that although QTD differed between healthy controls and patients
with dilated cardiomyopathy and ischemic heart disease, QTD was not correlated with
T‐wave residuum (TWR).20 TWR and several other ECG metrics for quantifying TDR have
been proposed and are summarized inTable. This suggests that structural heart disease
may be associated with more‐abnormal T‐wave loops, increased difficulty in measuring
T‐wave offset, and hence increased QTD indices. However, QTD per say may not represent
underlying heterogeneity in repolarization and does not itself confer increased cardiovascular
risk.
Table 1
Electrocardiographic Measures of Repolarization Heterogeneity
ECG Measure
Definition
Principal component analysis of the T wave
Ratio of the second to first eigenvalues of the spatial T‐wave vector generated from
the 12‐lead digital ECG
QRS‐T angle
Adding the mean vector representing all of the electrical forces produced by depolarization
and repolarization. This is accomplished by forming a parallelogram using the QRS
vector and the T‐wave vector as its sides; the diagonal of the figure is the spatial
ventricular gradient.
QT dispersion
Difference in ms between maximal and minimal QTc intervals from between 3 and 6 leads
in a simultaneous 12‐lead ECG
Simplified QRS‐T angle
Absolute difference between the QRS and T‐wave axes on the 12‐lead ECG
T peak T end
Time in ms between the peak of the T wave to the end of the T wave, as defined by
the intersection of the tangent to the down slope of the T wave and the isoelectric
line. Typically measured in V5
T‐wave area (total and late)
Area between the curve and baseline from J point to T end and T peak to T end, respectively
T‐wave residuum
Absolute value of the sum of the squares of the fourth to eighth eigenvalues of the
reconstructed T wave after singular value decomposition
T‐wave loop dispersion
Dissimilarities between the T‐wave shapes in individual leads, based on reconstruction
vectors of individual ECG leads
Total cosine R‐to‐T
Calculating cosine values between the 3‐dimensional R‐ and T‐wave loop vectors
ECG indicates electrocardiogram.
Mechanisms of Repolarization Heterogeneity in Congenital and Acquired LQTS
Much of the current understanding of the arrhythmic risk associated with repolarization
heterogeneity comes from work in patients with LQTS, both congenital and acquired.
In a landmark work, Moretti et al. linked congenital and physiology models of LQTS.
The investigators induced pluripotent stem cells from family members affected by LQTS‐1
and directed differentiation into cardiomyocytes. Differentiated cardiomyocytes exhibited
electrophysiologic features of the LQTS, including prolonged APD. This was associated
with a 70% to 80% reduction in IKs current and altered channel activation and deactivation
properties. This work linked congenital and physiological models of LQTS and helped
elucidate underlying molecular mechanisms of arrhythmogenicity.21
Congenital LQTS is associated with abnormal T‐wave morphologies on ECG that appear
to be specific to the different channel mutations and have even been suggested as
a screening tool.22 Work with the canine wedge‐preparation model revealed underlying
mechanisms for increased arrhythmogenicity of abnormal “LQTS‐type” T waves. Combined
IKr and IKs blockade simulating LQTS led to development of complex T waves with a
late “bump sign.”13 When an IKS blocker was used to prolong the QT interval in an
LQTS‐1 model, this was not associated with widening of the T wave, increased TDR,
or inducible TdP. However, addition of isoproterenol abbreviated the APD of epicardial
and endocardial cells, but not that of the M cell, resulting in widening of the T
wave and increase in TDR. Only after this exposure to isoproterenol was the myocardium
vulnerable to TdP, suggesting that heterogeneously increased APD across the ventricular
wall mediates vulnerability to TdP.23 IKr block with sotalol, simulating an LQTS‐2
model resulted in the development of broad‐ and low‐amplitude bifurcated T waves,
associated with increased TDR and TpTe in a rate‐dependent manner.24 Clinically, TDR
is increased in LQT2 more than LQT1, but LQTS‐1 patients show a heart‐rate–dependent
increase in TDR.25
When observed in other populations without congenital LQTS, the LQTS‐like T‐wave abnormalities
described previously seem to similarly represent increase arrhythmic risk. In patients
with bradycardia, LQTS‐2‐like T waves were more frequent in those who developed TdP.
Furthermore, increased TpTe was highly associated with development of TdP and performed
better as a predictor of TdP than either QTc or QT intervals.26 Findings were similar
in patients with drug‐induced QT‐prolongation, in whom TpTe did not correlate with
changes in QTc, suggesting that the arrhythmic risk is not mediated simply by prolonged
QTc.12 In patients initiated on sotalol, LQTS‐2‐like T‐wave changes developed, which
were independent of changes in QTc.27 And, when QT does prolong, dispersion of the
QT interval, rather than QT prolongation itself, seems to contribute most to arrhythmogenicity.28
Thus, work in both congenital and acquired LQTS populations suggested that other ECG
markers besides QT interval, including abnormal T‐wave morphologies and increased
TpTe are associated with abnormalities in repolarization heterogeneity, and even increased
arrhythmic risk.
Repolarization Heterogeneity as a Risk Factor for Mortality in the General Population
Repolarization heterogeneity is associated with adverse outcomes, including mortality,
in the general population. An analysis of 5812 healthy individuals over the age of
55 years in the Rotterdam Study showed that during a 4‐year follow‐up period, those
in the highest tertile of QTc dispersion (QTcD) had a nearly 2‐fold increased risk
of cardiac death, increased rates of sudden cardiac death (SCD), and overall 40% increased
mortality, compared to the lowest tertile.29 TpTe was independently associated with
SCD in the Oregon Sudden Unexplained Death Study, and a 1‐SD increase in TpTe increased
odds of SCD by 3.5‐fold.30 As part of the Finnish Health Study, Porthan et al. examined
several T‐wave morphology parameters, including principal component analysis (PCA)
ratio, T‐wave morphology dispersion, total cosine R‐to‐T (TCRT), and TWR. PCA ratio
and T‐wave morphology dispersion were independent predictors of all‐cause and cardiovascular
mortality in males. In females, TCRT and TWR were independent predictors of cardiovascular
mortality, and TWR was also an independent predictor of all‐cause mortality.31
T‐wave markers were also studied in a population of Native Americans as part of the
Strong Health Study, in which 1729 Native Americans were followed for a mean of 4.8 years.
Increased PCA ratio and TWR were significant predictors of cardiovascular mortality,
and TWR was an independent predictor of all‐cause mortality.32 The investigators also
demonstrated that QTD was a predictor of cardiovascular mortality in females.33 Finally,
Kardy et al. showed that in 6134 participants in the Rotterdam Study community‐based
cohort, increased QRS‐T angle (defined inTable) was independently associated with
increase hazard of cardiac death, sudden death, and total mortality.34
Repolarization Heterogeneity in Specific Populations
Repolarization heterogeneity has also been linked to adverse outcomes in numerous
cardiovascular disease populations. In patients presenting with acute coronary syndromes
(ACSs), repolarization heterogeneity has been associated with increased risk of fatal
arrhythmias. TpTe and TpTe/QT were significantly increased in ST‐elevation myocardial
infarction (STEMI) patients who experienced ventricular fibrillation (VF) within 24 hours
of admission.35 Eslami et al. found that percutaneous coronary intervention (PCI)
reduced both QTD and TpTe in patients presenting with STEMI.36 Interestingly, failure
of these ECG parameters to improve after reperfusion was associated with development
of major arrhythmias within 1 year.37 Post‐MI (myocardial infarction) patients who
show clinical or inducible ventricular tachycardia (VT) have longer TpTe than those
who are not inducible.38 TpTe is independently associated with all‐cause mortality
as well as risk of fatal cardiac arrhythmia within the first year after ACS.39, 40
Repolarization heterogeneity is also linked to adverse long‐term outcomes in ACS populations.
Haarmark et al. showed that pre‐PCI TpTe was associated with increased mortality in
STEMI patients during 22 months of follow‐up.41 In 334 survivors of acute MI followed
for 41 months, TCRT was an independent predictor of long‐term arrhythmic mortality.42
And, in patients who develop left ventricular systolic dysfunction post‐ACS, TpTe
is independently predictive of implantable cardioverter defibrillator therapy and
all‐cause mortality.43 Repolarization heterogeneity has also been linked to adverse
outcomes in genetic arrhythmia syndromes, congenital heart disease, and valvular heart
disease. In patients with Brudaga syndrome, TpTe and TpTe dispersion were prolonged
in patients with recurrent aborted SCD or syncope compared to asymptomatic individuals.44
TpTe and TpTe/QT were predictive of VT/VF inducibility in Brugada patients undergoing
programmed ventricular stimulation.45 Patients with repaired tetralogy of Fallot were
found to have increased QTcD and TpTe compared to healthy controls.46 QTD was increased
in patients with mitral valve prolapse and ventricular arrhythmias on Holter, compared
to matched controls. QTD and QTcD were increased in patients with aortic stenosis,
compared to controls, and were linearly related to disease severity.47 In patients
with hypertrophic cardiomyopathy, QTD and markers of T‐wave complexity were increased,
compared to controls, and were significantly greater in symptomatic patients.48, 49
TpTe has also been predictive of outcomes in other populations, including end‐stage
renal disease, LV hypertrophy (LVH), and hypertension, as summarized in Table S1.50,
51, 52
Mechanical Abnormalities in Patients With LQTS
Studies in LQTS have revealed that electrical repolarization abnormalities were accompanied
by abnormal myocardial mechanics. Nador et al. noted that patients with LQTS had a
more‐rapid early phase of ventricular contraction, as noted by a decreased time to
early contraction (Th1/2). Hence, they reached half maximal systolic contraction more
rapidly than controls. Furthermore, slow‐speed thickening in late systole, termed
TsTh, was increased in LQTS patients, indicating that they spend more time at a low
thickening rate. Taken together, rapid early contraction and prolonged slow thickening
phase represent a particular pattern of abnormal myocardial mechanisms that was observed
more frequently in symptomatic versus asymptomatic patients.53 The same group then
assessed the response of these contraction abnormalities to verapamil. Verapamil was
associated with increase in Th1/2 and reduction in TSTh, with normalization of the
abnormal thickening patterns at peak effect. They suggested that symptomatic LQTS
patients may have an abnormal increase in transcellular Ca levels which normalized
with administration of Ca‐channel blockers.54
Haugaa et al. used tissue Doppler to show that contraction duration was longer in
LQTS patients with past cardiac events compared to those without.55 Prolonged contraction
duration showed higher specificity and sensitivity than QTc at predicting events.
Greatest heterogeneity in contraction was observed in symptomatic LQTS mutation carriers
compared to asymptomatic carriers or controls. The investigators concluded that prolonged
myocardial contraction may lead to heterogeneous and delayed onset of the tissue Doppler
e′ wave, implying diastolic dysfunction.55 Strain analysis confirmed longer mean contraction
duration in symptomatic LQTS mutation carriers compared to asymptomatic carriers and
healthy controls. Contraction duration by longitudinal strain was longer than by circumferential
strain in symptomatic patients, suggesting increased transmural dispersion.56 Haguaa
et al. recently demonstrated reduced global longitudinal strain in subjects with LQTS
compared to healthy controls, as well as reduced e′ velocity (implying impaired LV
relaxation) and increased left atrial volume index.57 Table S2 summarizes studies
that have found associations between echocardiographic parameters and repolarization
heterogeneity.
Electromechanical Heterogeneity in Heart Failure
Early work by Alessandrini et al. revealed that electrocardiographic repolarization
changes in T‐wave amplitude and QT interval induced through ventricular pacing were
accompanied by echocardiographic changes in peak left ventricular filling rate and
isovolumic relaxation time (IVRT). Specifically, QT prolongation was associated with
increase IVRT and T‐wave amplitude was correlated with increase in peak LV filling
rate. These findings were not accompanied by changes in systolic function and thus
could not be explained on this basis. This link between electrical repolarization
and diastolic mechanics may be, in part, mediated by the effects of calcium handling.58
Specifically, increase in APD (as was observed with ventricular pacing) has been linked
to near doubling of cellular calcium influx and marked slowing of its decline.59 It
is thus not surprising that prolonged APD may be associated with changes in LV relaxation
and filling, processes that are calcium dependent. When relaxation and filling are
most abnormal, in end‐stage heart failure, mapping of coronary‐perfused LV wedge preparations
from human hearts confirmed prolongation of APD.60
During the progression from structural heart disease to heart failure, there is development
of an extensive amount of intercellular variability in Ca2+ kinetics. Disorganization
in T tubules and impairment in Ca2+ cycling accompany reductions in absolute strain
values and tissue Doppler velocities in spontaneously hypertensive rats.61 Initial
myocardial remodeling is associated with heterogeneous increase in Ca2+ transient
duration, which may, in part, explain the development of diastolic dysfunction as
the result of a prolonging in relaxation. These changes in strain and diastolic function
occur early in the remodeling process and precede the development of cardiac fibrosis
and overt LV systolic dysfunction (Figure 4).61
Figure 4
Proposed mechanism of electromechanical heterogeneity as a marker or contributor to
heart failure. Progression from normal (left‐hand side) to overt heart failure (right‐hand
side) is propagated by accumulation of risk factors such as hypertension, coronary
artery disease, and diabetes and their consequences, which include left ventricular
hypertrophy, heterogeneous dysregulation of Ca handling, and fibrosis. This manifests
as electrical repolarization heterogeneity and abnormal myocardial mechanics, which
includes diastolic dysfunction, reduction in peak longitudinal systolic strain, as
well as contraction‐relaxation heterogeneity observed using strain imaging. AP indicates
action potential; Endo, endocardial; Epi, epicardial; LVH, left ventricular hypertrophy;
M Cell, Masonic myocardial Moe cell.
Additionally, derangement in calcium cycling leads to increased vulnerability to intercellular
repolarization gradients and cellular Ca2+ alternans, a setup for reentrant and triggered
ventricular arrhythmias. Deficient sarcoplasmic reticulum Ca2+ uptake has been identified
in cardiac myocytes from failing human hearts and has been linked to a decrease in
expression and activity of the enzyme, Ca2+‐ATPase (SERCA2a). In animal models, transfection
of SERCA2a reduced Ca2+ alternans, decreasing susceptibility to ventricular arrhythmias.62
In the Calcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac
Disease (CUPID) gene therapy trial, intracoronary delivery of SERCA2a was associated
with decreased events, clinical improvement in heart failure symptoms, as well as
LV remodeling.63
Finally, it has recently been shown that QTc correlates with severity of diastolic
dysfunction on echocardiography in the general population, as well as in patients
with clinical symptoms of heart failure.64 Sauer et al. recently showed that increased
baseline TpTe was inversely associated with e′ velocity as well as peak exercise E/e′
ratio (Figure 5).65 Additionally, a linear association was noted between TpTe and
SD in time to peak radial strain, a measure of heterogeneity in contraction duration.
This finding was novel in establishing that the link between electrical repolarization
and myocardial contractility occurred in patients without LQTS or significant cardiomyopathy.66
“Excitation‐contraction” coupling may represent a unifying theory linking the subclinical
changes in myocardial dysfunction, calcium handling, and repolarization abnormalities
with the development of symptomatic heart failure syndromes.
Figure 5
Correlation between tissue Doppler and ECG markers of repolarization heterogeneity.
Shown here is an example of the relationship between tissue Doppler e′ velocity and
ECG TpTe interval. A, Normal e′ velocity (12.1 cm/s) and short TpTe interval (65 ms).
B, Abnormally reduced e′ velocity (7.8 cm/s) and long TpTe interval (115 ms). Asterisks
denote e′ wave on tissue Doppler tracings. Arrows denote TpTe interval on ECG tracings.
Reproduced from Sauer et al.65 Promotional and commercial use of the material in print,
digital, or mobile device format is prohibited without the permission from the publisher
Wolters Kluwer Health. ECG indicates electrocardiogram.
Unanswered Questions
Cellular work, animal models, and human cohorts have all suggested that heterogeneity
in myocardial repolarization exists, is increased in numerous disease states, and
appears to confer increased cardiovascular risk. Unfortunately to date there is no
consensus as to how best to measure repolarization heterogeneity in human subjects,
given that various techniques in open‐chest animal models have revealed conflicting
results. Furthermore, controversy also exists as to whether commonly used ECG measures,
such as TpTe or QTD, truly represent the repolarization heterogeneity itself or are
simply a surrogate for it. Future efforts should focus on prospectively assessing
outcomes to determine which of the currently identified ECG measures of repolarization
heterogeneity provides the greatest predictive value.
Furthermore, there is limited understanding currently as the role of repolarization
heterogeneity in the development or progression of heart failure syndromes. Recent
work revealed an association between abnormal TpTe duration and increased abnormalities
in diastolic function, as well as several other structural and mechanical myocardial
abnormalities. It is not yet clear whether increased repolarization heterogeneity
is a marker of myocardial mechanical dysfunction, let alone causative. Understanding
the role of repolarization heterogeneity in clinical heart failure symptoms represents
a promising avenue of future investigation. Demonstrating independent association
of repolarization heterogeneity with outcomes in heart failure populations would be
noteworthy, given that it may identify a subgroup of patients that could uniquely
be tailored for certain heart failure therapies. Similarly, whether normalization
of repolarization heterogeneity with medical therapy is associated with improved outcomes
in heart failure represents another avenue for further research. If improvements in
ejection fraction are associated with decrease in repolarization heterogeneity, then
perhaps identifying a pharmacological intervention to restore repolarization to a
more‐normal state may have a role in improving cardiovascular risk for numerous populations.
Conclusions
Accumulating evidence suggests that repolarization heterogeneity, a process initially
understood at the cellular level through work on canine wedge preparations, may play
a significant role in the pathophysiology of several cardiovascular conditions. Though
initially linked to increased risk of arrhythmia in patients with inherited LQTSs,
repolarization heterogeneity is now known to predict sudden death even in the general
population. Analysis of T‐wave characteristics on the ECG may help in risk stratification
in multiple cardiovascular conditions. More‐recent work linking repolarization heterogeneity
to abnormalities in myocardial mechanics may provide insight into development and
progression of clinical heart failure syndromes. Whether drugs that stabilize repolarization
heterogeneity can improve electromechanical abnormalities or clinical outcomes requires
further analysis. Additional studies are needed to identify other populations in which
repolarization heterogeneity may confer risk, and determine whether targeting these
electrical and mechanical abnormalities leads to improved cardiovascular outcomes.
Sources of Funding
Shah is supported by grants from the National Institutes of Health (R01 HL10577 and
R01 HL127028).
Disclosures
None.
Supporting information
Table S1. Studies of Clinical Outcomes Related to Increased Repolarization Heterogeneity
Table S2. Echocardiographic Parameters Associated With Repolarization Heterogeneity
Click here for additional data file.